EP1874281A2 - Optimisation de la pharmacodynamique d'agents therapeutiques pour le traitement de tissus vasculaires - Google Patents

Optimisation de la pharmacodynamique d'agents therapeutiques pour le traitement de tissus vasculaires

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Publication number
EP1874281A2
EP1874281A2 EP06740159A EP06740159A EP1874281A2 EP 1874281 A2 EP1874281 A2 EP 1874281A2 EP 06740159 A EP06740159 A EP 06740159A EP 06740159 A EP06740159 A EP 06740159A EP 1874281 A2 EP1874281 A2 EP 1874281A2
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EP
European Patent Office
Prior art keywords
cyp
modulator
antiproliferative
immunosuppressive agent
composition
Prior art date
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Withdrawn
Application number
EP06740159A
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German (de)
English (en)
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EP1874281A4 (fr
Inventor
Andrew J. Carter
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Individual
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Individual
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Publication of EP1874281A2 publication Critical patent/EP1874281A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2066—IL-10
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • the present invention relates to drugs and drug delivery systems for the prevention and treatment of vascular disease, and more particularly to drugs and drug delivery systems for the prevention and treatment of restenosis and neointimal hyperplasia.
  • Atherosclerosis the major cause of ischemic heart disease, involves the production of stenotic lesions on the interior walls of coronary arteries which limit or obstruct coronary blood flow.
  • One approach to treating an artery that has been constricted or occluded due to stenosis is percutaneous transluminal coronary angioplasty (PTCA) which is often followed by stent placement at the stenotic site.
  • PTCA percutaneous transluminal coronary angioplasty
  • a balloon catheter is inserted and expanded in the constricted portion of the vessel for clearing the blockage.
  • An increase in the use of this procedure is attributable to its relatively high success rate and its minimal invasiveness compared with coronary artery bypass surgery.
  • PTCA is not without its limitations.
  • PTCA Associated with PTCA is the abrupt closure of the treated vessel which may occur immediately after the procedure, and restenosis, or the renarrowing of the blood vessel, which occurs gradually following the procedure. About one-third of patients who undergo PTCA suffer from restenosis within about six months of the procedure. Restenosis is also a common problem in patients who have undergone saphenous vein bypass grafting.
  • the most effective treatment currently known for preventing restenosis is the drug- eluting stent.
  • Stents prevent negative remodeling but are associated with greater formation of neointima than balloon angioplasty.
  • These stents are coated or impregnated with one or more therapeutic agents, which either reduce or prevent a hyperproliferative response at the site of implantation.
  • the stent incorporates a biodegradable or nondegradable, polymer-based matrix to provide controlled release of therapeutic agents within the blood vessel.
  • the release mechanism of the drug from the polymeric material depends on the nature of the polymeric material and the drug itself. Release of the drug occurs by diffusion from or degradation of the polymeric material. Degradation of the polymeric material occurs through hydrolysis, which erodes the polymer into the fluid and hence releases the drug into the fluid as well.
  • antiproliferative and immunosuppressive agents have been employed with drug eluting stents to prevent restenosis. These include sirolimus, everolimus, ABT-578, FK 506, cyclosporine, mycophenolic acid (and its prodrug form as mycophenolate mofetil), and pimicrolimus. These agents are bacterial (sirolimus, FK 506) or fungal (cyclosporine A) metabolites that suppress lymphocyte function and cellular proliferation. Because of their toxicities, these agents cannot be used at maximally immunosuppressive doses. Accordingly, there is a need for safer versions of these agents as well as analogues thereof with higher immunosuppressive efficacy.
  • the antiproliferative effects of these compounds are dependent, in part, on dose, arterial tissue concentration, and the residence time of the drug in the arterial wall.
  • Drug loading on the strut surface of a stent is limited by surface area and polymer characteristics such as thickness of the coating.
  • the maximal drug load is severely constrained by the physical properties of the material.
  • drug elution from a solid matrix strut surface coating depends on the physical properties of the compound and of the polymer generally within principles of concentration dependent drug diffusion.
  • the arterial disposition of the compound may be influenced by the physical properties of the drug, active cellular mechanisms of drug-uptake, vascular morphology, redistribution to systemic circulation, and metabolism or degradation in the vessel wall.
  • cytochrome P450 is responsible for metabolism of some antiproliferative and immunosuppressive compounds.
  • Experimental studies have documented the expression of CYP in the endothelial and vascular smooth muscle cells of the arterial wall.
  • endothelial cells contain several heme-containing enzymes including CYP, nitric oxide synthase, and prostacyclin synthase. See Pfister et al., Rabbit aorta converts 15-HPETE to trihydroxyeicosatrienoic acids: potential role of cytochrome P450, Arch Biochem Biophys, 2003 Dec. l;420(l):142-52.
  • CYP 3 A4 which participates in the formation of nitric oxide from the compound isosorbide dinitrate and is present in the endothelium of human coronary arteries, has been found to be responsible for hepatic metabolism of compounds including sirolimus, ABT- 578, everolimus, FK506 and pimicrolimus and their analogs.
  • sirolimus is metabolized via the CYP 3A4 to the inactive metabolites 41 -hydroxy and 39- demethyl sirolimus which do not exhibit any antiproliferative or immunosuppressive properties.
  • Clotrimazole is an example of a non-specific CYP inhibitor while ebastine and terfenadone specifically inhibit CYP 2J2.
  • Compounds that block or reduce the CYP 3A4 are known to prolong the half-life of sirolimus and its analogs. For example, ketoconazole, oleandomycin and gestodene are selective inhibitors of CYP3A4 that inhibit metabolism of FK 506 and sirolimus.
  • the present invention comprises a combination of two compounds wherein a first compound acts to suppress lymphocyte function and cellular proliferation and a second compound inhibits the formation of and/or activity of an enzyme involved in the metabolism of the first compound.
  • the first compound which is an antiproliferative- immunosuppressive agent, is useful in inhibiting restenosis.
  • the second compound maintains the activity of the first compound by either inhibiting an enzyme involved in metabolizing the first compound or inhibiting the formation of compounds which are involved in the metabolism of the first compound.
  • An aspect of the invention is the local inhibition of CYP 3A4 in the arterial wall thereby prolonging the tissue half-life, reducing the formation of degradants, and inhibiting other mechanisms which results in metabolism of compounds such as sirolimus.
  • Another aspect of the invention is the preservation of compounds in the vessel wall via inhibition of CYP which results in reducing the presence of metabolites or degradants associated with idiosyncratic or other adverse drug reactions.
  • Still another aspect of the invention provides specific CYP modulators that alter the expression of the CYP and therefore the metabolism of a particular agent such as an immunosuppressive and/or antiproliferative compound.
  • Still yet another aspect of the invention is providing such CYP modulators to enable the use of antiproliferative-immunosuppressive agents at dosages having lower toxicity levels and/or which improve the efficacy of the antiproliferative agents by altering the tissue or cellular pharmacodynamics of the compound.
  • Another aspect of the invention is a CYP modulator and antiproliferative agent combination used in the context of PTCA and/or stent placement within a vessel, e.g., at a target site within the wall of the artery being treated.
  • Another aspect of the present invention is the combination of parenteral or local agents that modify CYP3A4 in order to increase the arterial tissue concentration and/or tissue half-life of stent-based, antiproliferative-immunosuppressive agents.
  • FIG. 1 is a schematic illustration of a stent coated with an exemplary CYP inhibitor, e.g., ketoconazole, and an exemplary suppressor of cell proliferation, e.g. sirolimus. Biochemical interactions are also schematically shown.
  • ketoconazole inhibits CYP 3A4 and thereby inhibits the metabolism of sirolimus to 39- demethyl sirolimus.
  • Sirolimus inhibits cytokines and modulates cyclin dependent kinases involved in cellular proliferation.
  • the present invention describes methods to modify arterial biotransformation of drugs to metabolites without known biological or potentially toxic effects by altering metabolic pathways of certain compounds in the vessel wall.
  • the methods and compositions of the invention enable the application of stent-based delivery of antiproliferative-immunosuppressive drugs at lower doses, enhance efficacy via sustained arterial tissue concentrations of the drug, and reduce the likelihood for idiosyncratic or hypersensitivity reactions.
  • the present invention combines the parenteral or local delivery of agents which inhibit or induce CYP activity or production in the arterial wall and thereby increase the arterial tissue concentration of and/or the tissue half-life of a locally delivered antiproliferative-immunosuppressive drug, as well as alter the production of metabolites in the arterial wall.
  • the metabolic activity of CYP in the arterial wall is inhibited or induced by systemic or local administration of the CYP inhibitor or inducer, respectively.
  • the CYP inhibitor/inducer is delivered locally to the artery, e.g., via a balloon catheter, a stent or other medical implant.
  • the CYP inhibitor/inducer may be coated directly to the entire exposed surface of the stent or a portion thereof, which may have a metal or non-polymeric structure, or be embedded within a biodegradable or non-biodegradable polymer matrix applied to the stent body.
  • the CYP inhibitor/inducer may be combined with one or more antiproliferative and/or immunosuppressive compounds in equimolar or varying concentrations to achieve the desired biological effect, i.e., enhance the half-life of the antiproliferative and/or immunosuppressive agent and thereby inhibit restenosis.
  • the coating or embedding of the CYP inhibitor or inducer may be provided in a manner to allow for any sequence of drug delivery.
  • the coating or embedding of the drugs may be done to provide for an initial delivery of the CYP inhibitor/inducer followed by delivery of the antiproliferative and/or immunosuppressive compound.
  • the drugs may be coated or embedded in a manner which provides for the simultaneous delivery of the CYP inhibitor/inducer and the antiproliferative/immunosuppressive compound.
  • the drugs may be coated or embedded in a manner which provides for the initial delivery of the antiproliferative/immunosuppressive compound followed by delivery of the CYP inhibitor/inducer.
  • a CYP inhibitor in the arterial wall may facilitate other mechanisms of drug metabolism, thereby reducing the presence of metabolites or degradants that may be associated with idiosyncratic or other adverse drug reactions.
  • the CYP inhibitor used with the methods of the present invention is a CYP 450 3 A4 inhibitor.
  • the CYP 450 3A4 inhibitor is ketoconazole, and the antiproliferative/ immunosuppressive compound is sirolimus.
  • ketoconazole may range from about 0.0001 to about 100 mg per millimeter of stent length or square millimeter of the medical implant surface
  • sirolimus may range from about 0.0001 to about 100 mg per millimeter of stent length or square millimeter of the medical implant surface.
  • Drugs or compounds that induce or increase CYP substrate can promote the metabolism of other drugs or compounds that depend on this metabolic pathway.
  • a CYP inducer would increase the arterial metabolism of several drugs resulting in a reduced tissue half-life.
  • the CYP 450 inducer is rifampin and the immunosuppressive compound is ABT-578, a tetrazole ring analog of siroiimus with a prolonged tissue half-life.
  • the dose of ABT-578 may range from about 0.0001 to about 100 mg per millimeter of stent length or square millimeter of the medical implant surface.
  • the dose of rifampin may range from about 0.0001 to about 100 mg per millimeter of stent length or square millimeter of the medical implant surface.
  • CYP inhibitors that might be used in combination with siroiimus or an analog thereof include but are not limited to amiodarone, azithromycin, cimetidine, ciprofloxacin, imidazole antifungals, clarithromycin, clotrimazole, calcium channel blockers such as nifedipine, diltiazem and verapamil, delaviridine, diethyl- dithiocarbamate, erythromycin, fluconazole, fluvoxamine, gestodene, grapefruit juice, indinavir, interleukin-10, itraconazole, mibefradil, mifepristone, nefazodone, nelfinavir, naringen, norfloxacin, norfiuoxetine, ritonavir, saquinavir, and troleandomycin.
  • amiodarone azithromycin, cimetidine, ciprofloxacin, imi
  • CYP inducers that might be used in combination with siroiimus or an analog include but are not limited to the herbal medicine St. John's Wort, barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, phenobarbital, phenytoin, pioglitazone, and troglitazone.
  • ABT-578 biolimus A9, everolimus, FK506, pimicrolimus, methotrexate, and steroids.
  • compositions of the present invention may be delivered with a combination of delivery routes.
  • the immunosuppressive compound may be delivered locally as a coating on a medical implant, e.g., a stent, while the CYP modulator may be delivered systemically, e.g., through oral and/or parenteral delivery.
  • the oral or ingestible form of the modulator may be a liquid or solid (pill form).
  • Parenteral administration may be via intravenous, intra-arterial, intra-articular, intracardiac, subcutaneous, intradermal, intraspinal or epidural, or intramuscular injection. Oral administration is advantageous in that it can be done conveniently by the patient, however, but is clearly not suitable for continuous administration.
  • Parenteral administration is not as convenient for the patient and may require the assistance of a medical professional; however, it can be administered continuously or for periods of continuous delivery.
  • the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Un implant, notamment une endoprothèse, est revêtu du polymère biodégradable ou non biodégradable contenant un agent antiprolifératif/immunosuppresseur et un composé réduisant la vitesse de métabolisme de l'agent antiprolifératif/immunosuppresseur avec pour effet l'inhibition de la resténose.
EP06740159A 2005-03-30 2006-03-30 Optimisation de la pharmacodynamique d'agents therapeutiques pour le traitement de tissus vasculaires Withdrawn EP1874281A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/096,241 US20060222627A1 (en) 2005-03-30 2005-03-30 Optimizing pharmacodynamics of therapeutic agents for treating vascular tissue
PCT/US2006/011850 WO2006105374A2 (fr) 2005-03-30 2006-03-30 Optimisation de la pharmacodynamique d'agents therapeutiques pour le traitement de tissus vasculaires

Publications (2)

Publication Number Publication Date
EP1874281A2 true EP1874281A2 (fr) 2008-01-09
EP1874281A4 EP1874281A4 (fr) 2009-01-14

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US20110207660A1 (en) * 2008-08-07 2011-08-25 Schering Corporation Pharmaceutical formulations of an hcv protease inhibitor in a solid molecular dispersion
SG11201507406YA (en) * 2013-03-15 2015-10-29 Biosensors Int Group Ltd Purification of rapamycin derivatives
CN110384854B (zh) * 2019-08-02 2020-12-01 上海心玮医疗科技有限公司 一种药物代谢可控的药物球囊及其制备方法

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